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var scrollPosition = $(window).height() + $(window).scrollTop(); if($(this).scrollTop() > 200){ $('.search_section_wrap').addClass('fixed'); }else{ $('.search_section_wrap').removeClass('fixed'); } }); </script> <div class="sub_content clear"> <div class="sub_left"> <div class="sub_tit clear"> <h2>Article</h2> </div> <link rel='stylesheet' type='text/css' href='/journal/css/style.css' /> <script type='text/javascript' src='/journal/js/script.js?v=20220520'></script> <script type="text/javascript"> //<![CDATA[ // Blue !!! 2012-05-10 페이지내 section 링크 function ViewNamePositionFun(ID) { location.href = "/journal/view.html?uid=1032&vmd=Full" + ID; return false; } // Blue !!! 2012-05-10 참고문헌 연결시 배경색을 넣음. var tmpID = ""; function ViewReferencePositionFun(ID) { if (tmpID) document.getElementById(tmpID.substring(1)).style.backgroundColor = "#FFFFFF"; location.href = "/journal/view.html?uid=1032&vmd=Full" + ID; document.getElementById(ID.substring(1)).style.backgroundColor = "#F2F2FF"; tmpID = ID; } //]]> </script> <div class="section01"> <h2></h2> </div> <div id="origin_a"> <div class="inner_content">  <script src="https://crossmark-cdn.crossref.org/widget/v2.0/widget.js"></script> <a data-target="crossmark"><img src="//crossmark-cdn.crossref.org/widget/v2.0/logos/CROSSMARK_Color_horizontal.svg" width="150" /></a> <div class="origin_section01"><p>J Obes Metab Syndr 2023; 32(4): 289-302</p><p><strong>Published online</strong> December 30, 2023 <a href='https://doi.org/10.7570/jomes23054' target='_blank'>https://doi.org/10.7570/jomes23054</a></p><p>Copyright © Korean Society for the Study of Obesity.</p> </div> <div class="origin_section02"><h2>Mitochondrial Quality Control: Its Role in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)</h2><p class="write-authors">Soyeon Shin, Jaeyoung Kim, Ju Yeon Lee, Jun Kim, Chang-Myung Oh <a href='https://orcid.org/0000-0001-6681-4478' target='_blank' title="Chang-Myung Oh"><img src='/journal/img/orcid.png' style='vertical-align: bottom;'></a><sup>*</sup></p><div class="text-left"><a href="#n" class="author-info-btn"><i class="xi-angle-right"></i>Author Affiliations</a></div><p class="author-info">Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Korea</p><p><strong>Correspondence to:</strong><br>Chang-Myung Oh<br><a href="https://orcid.org/0000-0001-6681-4478" target="_blank" rel="noopener">https://orcid.org/0000-0001-6681-4478</a><br>Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, 123 Cheomdangwagi-ro, Buk-gu, Gwangju 61005, Korea<br>Tel: +82-62-715-5377<br>Fax: +82-62-715-5309<br>E-mail: <a href="mailto:cmoh@gist.ac.kr" target="_blank" rel="noopener">cmoh@gist.ac.kr</a></p><div class="origin_date"><strong >Received</strong>: August 25, 2023; <strong >Reviewed </strong>: September 27, 2023; <strong >Accepted</strong>: September 30, 2023</div><p class="origin_txt">This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (<a href="http://creativecommons.org/licenses/by-nc/4.0/" onclick="window.open(this.href);return false;" class="link_color">http://creativecommons.org/licenses/by-nc/4.0/</a>) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.</p></div> <div class="origin_section03" id="body00"> <div class="section03_tit clear"> <h3>Abstract</h3> <div class="goto_layer"> <a href="#n">Go to <i class="xi-caret-down-min"></i></a> <ul class="go_list"><li><a class="list_name" href="#body00">Abstract</a></li><li><a class="list_name" href="#body01">INTRODUCTION</a></li><li><a class="list_name" href="#body02">ROLE OF MITOCHONDRIA IN THE LIVER</a></li><li><a class="list_name" href="#body03">MITOCHONDRIAL DYSFUNCTION-MEDIATED METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE</a></li><li><a class="list_name" href="#body04">NEW THERAPEUTICS FOR MASLD</a></li><li><a class="list_name" href="#body05">CONCLUSION</a></li><li><a class="list_name" href="#body06">CONFLICTS OF INTEREST</a></li><li><a class="list_name" href="#body07">ACKNOWLEDGMENTS</a></li><li><a class="list_name" href="#body08">AUTHOR CONTRIBUTIONS</a></li><li><a class="list_name" href="#body09">Figure</a></li><li><a class="list_name" href="#body10">Table</a></li><li><a class="list_name" href="#body11">References</a></li></ul> </div> </div><div class="go_section" id="fulltext_Area"><p style="margin:5px;">Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, is characterized by hepatic steatosis and metabolic dysfunction and is often associated with obesity and insulin resistance. Recent research indicates a rapid escalation in MASLD cases, with projections suggesting a doubling in the United States by 2030. This review focuses on the central role of mitochondria in the pathogenesis of MASLD and explores potential therapeutic interventions. Mitochondria are dynamic organelles that orchestrate hepatic energy production and metabolism and are critically involved in MASLD. Dysfunctional mitochondria contribute to lipid accumulation, inflammation, and liver fibrosis. Genetic associations further underscore the relationship between mitochondrial dynamics and MASLD susceptibility. Although U.S. Food and Drug Administration-approved treatments for MASLD remain elusive, ongoing clinical trials have highlighted promising strategies that target mitochondrial dysfunction, including vitamin E, metformin, and glucagon-like peptide-1 receptor agonists. In preclinical studies, novel therapeutics, including nicotinamide adenine dinucleotide<sup>+</sup> precursors, urolithin A, spermidine, and mitoquinone, have shown beneficial effects, such as improving mitochondrial quality control, reducing oxidative stress, and ameliorating hepatic steatosis and inflammation. In conclusion, mitochondrial dysfunction is central to MASLD pathogenesis. The innovative mitochondria-targeted approaches discussed in this review offer a promising avenue for reducing the burden of MASLD and improving global quality of life.</p><p><strong>Keywords</strong>: Metabolic dysfunction-associated steatotic liver disease, Mitochondria, Mitochondrial quality control</p></div></div> <div class="origin_section03" id="body01"> <div class="section03_tit clear"> <h3>INTRODUCTION</h3> <div class="goto_layer"> <a href="#n">Go to <i class="xi-caret-down-min"></i></a> <ul class="go_list"><li><a class="list_name" href="#body00">Abstract</a></li><li><a class="list_name" href="#body01">INTRODUCTION</a></li><li><a class="list_name" href="#body02">ROLE OF MITOCHONDRIA IN THE LIVER</a></li><li><a class="list_name" href="#body03">MITOCHONDRIAL DYSFUNCTION-MEDIATED METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE</a></li><li><a class="list_name" href="#body04">NEW THERAPEUTICS FOR MASLD</a></li><li><a class="list_name" href="#body05">CONCLUSION</a></li><li><a class="list_name" href="#body06">CONFLICTS OF INTEREST</a></li><li><a class="list_name" href="#body07">ACKNOWLEDGMENTS</a></li><li><a class="list_name" href="#body08">AUTHOR CONTRIBUTIONS</a></li><li><a class="list_name" href="#body09">Figure</a></li><li><a class="list_name" href="#body10">Table</a></li><li><a class="list_name" href="#body11">References</a></li></ul> </div> </div><div class="go_section" id="fulltext_Area"><div style="margin:5px;"><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a new name for non-alcoholic fatty liver disease (NAFLD) to focus on steatotic liver disease associated with metabolic dysfunction and includes the presence of at least one of five cardiometabolic risk factors of obesity, glucose intolerance, dyslipidemia, and hypertension.<sup><span class='xref'><a href="#B1" class="tooltip-img" title="">1</a></span></sup> With a global prevalence of approximately 30%, MASLD is the most common chronic liver disease worldwide.<sup><span class='xref'><a href="#B2" class="tooltip-img" title="">2</a></span></sup> A recent study has highlighted a significantly rapid increase in the number of patients with MASLD.<sup><span class='xref'><a href="#B3" class="tooltip-img" title="">3</a></span></sup> Projections based on previous estimates have indicated a doubling of MASLD cases in the United States by 2030.<sup><span class='xref'><a href="#B4" class="tooltip-img" title="">4</a></span>,<span class='xref'><a href="#B5" class="tooltip-img" title="">5</a></span></sup> Approximately 60% to 80% of individuals with type 2 diabetes mellitus and 80% of individuals with obesity are affected by MASLD.<sup><span class='xref'><a href="#B6" class="tooltip-img" title="">6</a></span>,<span class='xref'><a href="#B7" class="tooltip-img" title="">7</a></span></sup> Although obesity is closely related to MASLD,<sup><span class='xref'><a href="#B8" class="tooltip-img" title="">8</a></span></sup> lean individuals can experience the disease, which is a significant health concern. The development of lean MASLD can be influenced by loss of muscle mass and visceral obesity among other factors.<sup><span class='xref'><a href="#B9" class="tooltip-img" title="">9</a></span></sup></p> <p>The hallmark of MASLD is greater than 5% fat accumulation in the liver upon histological examination. This steatosis can progress to inflammatory metabolic dysfunction-associated steatohepatitis (MASH), followed by fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), culminating in liver failure.<sup><span class='xref'><a href="#B10" class="tooltip-img" title="">10</a></span></sup> In patients with MASLD, 41.9% experience steatohepatitis; approximately 32% with MASH experience liver fibrosis progression or regression.<sup><span class='xref'><a href="#B11" class="tooltip-img" title="">11</a></span></sup> This complex situation demonstrates how MASLD contributes to the increasing incidence of hepatic cirrhosis and HCC worldwide. In addition, MASLD was associated with risk of all-cause and cardiovascular death in a large population-based cohort of Korean adults.<sup><span class='xref'><a href="#B12" class="tooltip-img" title="">12</a></span></sup> Owing to the serious effects associated with these illnesses, it is necessary to explore the causes of MASLD and to determine ways to develop effective therapeutic interventions.</p> <p>Several studies have shown the existence of molecular, biochemical, and biophysical perturbations in mitochondrial dynamics relevant to MASLD.<sup><span class='xref'><a href="#B13" class="tooltip-img" title="">13</a></span>-<span class='xref'><a href="#B15" class="tooltip-img" title="">15</a></span></sup> Despite the insights gained from these studies, the mechanistic orchestration leading to mitochondrial dysfunction and the triggering of NAFLD pathogenesis and progression remain to be elucidated. In this review, we discussed the recent findings on the role of mitochondria in metabolism and their clinical implications in MASLD treatment.</p></div></div></div> <div class="origin_section03" id="body02"> <div class="section03_tit clear"> <h3>ROLE OF MITOCHONDRIA IN THE LIVER</h3> <div class="goto_layer"> <a href="#n">Go to <i class="xi-caret-down-min"></i></a> <ul class="go_list"><li><a class="list_name" href="#body00">Abstract</a></li><li><a class="list_name" href="#body01">INTRODUCTION</a></li><li><a class="list_name" href="#body02">ROLE OF MITOCHONDRIA IN THE LIVER</a></li><li><a class="list_name" href="#body03">MITOCHONDRIAL DYSFUNCTION-MEDIATED METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE</a></li><li><a class="list_name" href="#body04">NEW THERAPEUTICS FOR MASLD</a></li><li><a class="list_name" href="#body05">CONCLUSION</a></li><li><a class="list_name" href="#body06">CONFLICTS OF INTEREST</a></li><li><a class="list_name" href="#body07">ACKNOWLEDGMENTS</a></li><li><a class="list_name" href="#body08">AUTHOR CONTRIBUTIONS</a></li><li><a class="list_name" href="#body09">Figure</a></li><li><a class="list_name" href="#body10">Table</a></li><li><a class="list_name" href="#body11">References</a></li></ul> </div> </div><div class="go_section" id="fulltext_Area"><div style="margin:5px;"><h3>Mitochondria as a metabolic hub in the liver</h3> <p>The liver is a central organ of metabolic adaptability in humans and is characterized by dynamic responsiveness to shifts in energy demand and availability. Within hepatocytes, mitochondria are critical organelles that are involved in energy production and act as metabolic hubs.<sup><span class='xref'><a href="#B16" class="tooltip-img" title="">16</a></span>,<span class='xref'><a href="#B17" class="tooltip-img" title="">17</a></span></sup> Mitochondria play a role in hepatic-specific anabolic pathways, including <italic>de novo</italic> lipogenesis, gluconeogenesis, and nonspecific one-carbon metabolism, and in catabolic pathways such as tricarboxylic acid and urea cycles, β-oxidation, ketogenesis, and the electron transport chain linked to the production of reactive oxygen species (ROS).<sup><span class='xref'><a href="#B16" class="tooltip-img" title="">16</a></span></sup></p> <p>Amid this intricate adaptation, hepatocyte mitochondria have emerged as key collaborators that finely tune metabolic flexibility. When these delicate processes are disrupted, mitochondrial problems cause several cellular stresses, such as increased ROS production, impaired oxidative phosphorylation (OxPhos), and a deranged immune response.<sup><span class='xref'><a href="#B18" class="tooltip-img" title="">18</a></span></sup> These disturbances can lead to the development of metabolic diseases in the liver.</p> <h3>Mitochondrial oxidative stress</h3> <p>Recent studies have highlighted the importance of mitochondrial processes, specifically oxidative stress, mitophagy, and quality control, in the balance between liver function and disease progression.<sup><span class='xref'><a href="#B19" class="tooltip-img" title="">19</a></span>,<span class='xref'><a href="#B20" class="tooltip-img" title="">20</a></span></sup> Mitochondria are essential for energy production. OxPhos, which occurs within mitochondria, is a significant source of oxidative stress as it generates adenosine triphosphate (ATP), superoxide anions, and hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) as byproducts.<sup><span class='xref'><a href="#B19" class="tooltip-img" title="">19</a></span>,<span class='xref'><a href="#B21" class="tooltip-img" title="">21</a></span></sup> Increased β-oxidation within mitochondria and peroxisomes is also a source of ROS production. In addition to the mitochondria, the endoplasmic reticulum (ER) can also produce ROS.<sup><span class='xref'><a href="#B19" class="tooltip-img" title="">19</a></span></sup></p> <p>Antioxidant defense systems consist of enzymatic and nonenzymatic components.<sup><span class='xref'><a href="#B22" class="tooltip-img" title="">22</a></span></sup> The enzymatic components comprise a collection of enzymes that effectively counteract ROS production. Prominent examples include alpha-dioxygenase, ascorbate peroxidase, superoxide dismutase, catalase, glutathione peroxidase (GPX), and glutathione (GSH) reductase.<sup><span class='xref'><a href="#B22" class="tooltip-img" title="">22</a></span></sup> In contrast, nonenzymatic elements include small molecules such as GSH, ascorbic acid (vitamin C), retinol (vitamin A), melatonin, and tocopherol (vitamin E).<sup><span class='xref'><a href="#B22" class="tooltip-img" title="">22</a></span></sup> These molecules act as electron acceptors and protect biomolecules and cellular structures from ROS-induced damage.</p> <p>Excessive ROS production overwhelms antioxidant defenses, leading to oxidative stress and subsequent cellular damage. Additionally, the inflammatory response significantly affects oxidative stress.<sup><span class='xref'><a href="#B23" class="tooltip-img" title="">23</a></span></sup> Disruption of the redox balance impairs insulin signaling and lipid metabolism, leading to lipid accumulation and liver inflammation.<sup><span class='xref'><a href="#B19" class="tooltip-img" title="">19</a></span></sup> These are important processes in the progression of liver injury. When the liver is injured, oxidative stress triggers the activation of redox-sensitive transcription factors, such as nuclear factor kappa B (NF-κB), early growth factor 1, and activator protein 1. As a result, an inflammatory response follows, coupled with the initiation of cell death pathways within hepatocytes.<sup><span class='xref'><a href="#B19" class="tooltip-img" title="">19</a></span>,<span class='xref'><a href="#B24" class="tooltip-img" title="">24</a></span>,<span class='xref'><a href="#B25" class="tooltip-img" title="">25</a></span></sup> Taken together, these findings highlight the importance of proper regulation of ROS levels and antioxidant defenses in cellular health and prevention of harmful outcomes.<sup><span class='xref'><a href="#B26" class="tooltip-img" title="">26</a></span></sup></p> <p>In response to oxidative stress, mitochondria possess an efficient system to repair oxidatively damaged macromolecules.<sup><span class='xref'><a href="#B27" class="tooltip-img" title="">27</a></span></sup> The lipid composition of mitochondrial membranes makes them highly prone to ROS-induced oxidative damage. In particular, cardiolipin (CL), a glycerophospholipid dimer within the inner mitochondrial membrane, serves as an anchoring point for respiratory supercomplexes and mitochondrial DNA (mtDNA) during replication and mitochondrial protein transport.<sup><span class='xref'><a href="#B28" class="tooltip-img" title="">28</a></span></sup> Maintaining the integrity of CL is critical for mitochondrial health because its oxidation is associated with cytochrome c release and increased mitochondrial membrane permeability to apoptotic factors.</p> <p>Oxidative modification of CL and its degradation products attenuates respiratory chain complex activities while promoting mitochondrial pore opening and permeability transitions. As damaged CL is detrimental to mitochondria, oxidized CL is rapidly degraded.<sup><span class='xref'><a href="#B28" class="tooltip-img" title="">28</a></span></sup> CL phospholipase hydroxysteroid 17-β dehydrogenase 10 was recently shown to mediate the degradation of oxidized CL.<sup><span class='xref'><a href="#B28" class="tooltip-img" title="">28</a></span>,<span class='xref'><a href="#B29" class="tooltip-img" title="">29</a></span></sup> Key enzymes such as GPX 4 counteract mitochondrial lipid peroxidation through direct detoxification of membrane lipid hydroperoxides.<sup><span class='xref'><a href="#B30" class="tooltip-img" title="">30</a></span></sup> In addition, ubiquinol is involved in the repair of peroxidized mitochondrial lipids, and dihydroorotate dehydrogenase plays a role in generating ubiquinol to counteract the effects of lipid peroxidation and ferroptosis.<sup><span class='xref'><a href="#B31" class="tooltip-img" title="">31</a></span>,<span class='xref'><a href="#B32" class="tooltip-img" title="">32</a></span></sup></p> <h3>Mitochondrial quality control</h3> <p>In MASLD, several factors contribute to excessive ROS production, including decreased expression of intracellular antioxidant enzymes, GSH depletion, imbalances in ROS production and detoxification due to inflammatory reactions, and leukocyte accumulation in the liver. The abundance of ROS generated by these processes disrupts the balance of antioxidant defense systems in the liver, exacerbating oxidative damage.<sup><span class='xref'><a href="#B33" class="tooltip-img" title="">33</a></span></sup> Therefore, an appropriate ROS balance is essential for mitochondrial integrity and function through mitochondrial quality control (MQC) processes.<sup><span class='xref'><a href="#B34" class="tooltip-img" title="">34</a></span></sup></p> <p>Mitochondria have a diverse array of mechanisms for maintenance of their intricate homeostasis.<sup><span class='xref'><a href="#B35" class="tooltip-img" title="">35</a></span></sup> First, they possess an intrinsic proteolytic system that degrades misfolded proteins that can potentially compromise mitochondrial function.<sup><span class='xref'><a href="#B36" class="tooltip-img" title="">36</a></span></sup> Mitochondrial proteases and the cytosolic ubiquitin–proteasome system (UPS) act as the first-line of cellular defense by eliminating damaged, oxidized, or misfolded mitochondrial protein.<sup><span class='xref'><a href="#B37" class="tooltip-img" title="">37</a></span></sup> There are two membrane-bound ATPases associated with diverse cellular activities (AAA) that are responsible for quality control along the inner mitochondrial membrane and are part of the AAA+ superfamily.<sup><span class='xref'><a href="#B38" class="tooltip-img" title="">38</a></span></sup> Matrix AAA protease targets the matrix, whereas intermembrane AAA protease targets the intermembrane spac.<sup><span class='xref'><a href="#B38" class="tooltip-img" title="">38</a></span></sup> The OMA1 zinc metallopeptidase (OMA1) and Lon protease also contribute to this process. The ClpXP protease, a well-characterized and established AAA+ protease, comprises hexamers of AAA+ ATPase (ClpX) and tetradecameric peptidase (ClpP)<sup><span class='xref'><a href="#B39" class="tooltip-img" title="">39</a></span></sup> and regulates the mitochondrial unfolded protein response (mtUPR).<sup><span class='xref'><a href="#B40" class="tooltip-img" title="">40</a></span>-<span class='xref'><a href="#B43" class="tooltip-img" title="">43</a></span></sup> Notably, the cytosolic UPS also aids in MQC by detecting and eliminating misdirected or misfolded proteins. To restore cellular balance, cytosolic UPS also degrades mitochondrial outer membrane proteins in a process termed outer mitochondrial membrane-associated degradation, which is similar to ER-associated protein degradation.<sup><span class='xref'><a href="#B44" class="tooltip-img" title="">44</a></span>,<span class='xref'><a href="#B45" class="tooltip-img" title="">45</a></span></sup></p> <p>Second, the continuous process of mitochondrial dynamics involving fission and fusion provides a dynamic repair mechanism that eliminates dysfunctional components through fission-driven segregation and promotes material exchange between intact mitochondria through fusion-mediated interaction.<sup><span class='xref'><a href="#B46" class="tooltip-img" title="">46</a></span></sup> Fission and fusion are essential for maintaining mitochondrial integrity. During fission, damaged portions are selectively removed, leaving healthy segments. Conversely, fusion structurally complements impaired mitochondria and facilitates the exchange of mtDNA. Proteins regulating mitochondrial dynamics are significantly associated with MASLD. The levels of proteins that are associated with mitochondrial dynamics, such as dynamin-related protein 1 (Drp1), mitochondrial fission 1 protein (Fis1), and mitofusion-2, decrease in mice after 6 months of a Western diet,<sup><span class='xref'><a href="#B47" class="tooltip-img" title="">47</a></span>,<span class='xref'><a href="#B48" class="tooltip-img" title="">48</a></span></sup> whereas overexpression of Drp1 and Fis1 can alleviate hepatic injury.<sup><span class='xref'><a href="#B13" class="tooltip-img" title="">13</a></span></sup></p> <p>Third, oxidative stress causes a group of mitochondria to bud and create mitochondria-derived vesicles (MDVs). MDVs show remarkable size uniformity, ranging from 70 to 150 nm, and undergo cleavage independent of Drp1. MDVs bifurcate into two pathways: they are either directed to the late endosome/multivesicular body and then combine with lysosomes to coordinate the breakdown of oxidized mitochondrial proteins within the MDVs,<sup><span class='xref'><a href="#B49" class="tooltip-img" title="">49</a></span>-<span class='xref'><a href="#B51" class="tooltip-img" title="">51</a></span></sup> or they embark on a distinct trajectory, targeting a specialized subset of peroxisomes.<sup><span class='xref'><a href="#B52" class="tooltip-img" title="">52</a></span></sup> The PTEN induced kinase 1 (PINK1) and cytosolic ubiquitin E3 ligase parkin are required for the binding of MDVs to lysosomes.<sup><span class='xref'><a href="#B53" class="tooltip-img" title="">53</a></span></sup> Both PINK1 and parkin are mutated in familial cases of Parkinson’s disease and function in a shared pathway in MQC.<sup><span class='xref'><a href="#B53" class="tooltip-img" title="">53</a></span></sup></p> <p>Disrupted mitochondria undergo a transformative pathway, coalescing into mitochondrial spheroids and acquiring lysosomal markers, potentially serving as an alternative pathway for eliminating compromised mitochondria. Mitophagy is the process of autophagy in which damaged mitochondria are engulfed and degraded within lysosomes as they become irreparable through fission and fusion.<sup><span class='xref'><a href="#B26" class="tooltip-img" title="">26</a></span>,<span class='xref'><a href="#B54" class="tooltip-img" title="">54</a></span></sup> Dysregulated mitophagy compromises mitochondrial turnover and quality control, leading to impaired OxPhos and energy production, culminating in abnormal lipid metabolism and hepatic steatosis and contributing to the pathogenesis of metabolic disorders.</p></div></div></div> <div class="origin_section03" id="body03"> <div class="section03_tit clear"> <h3>MITOCHONDRIAL DYSFUNCTION-MEDIATED METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE</h3> <div class="goto_layer"> <a href="#n">Go to <i class="xi-caret-down-min"></i></a> <ul class="go_list"><li><a class="list_name" href="#body00">Abstract</a></li><li><a class="list_name" href="#body01">INTRODUCTION</a></li><li><a class="list_name" href="#body02">ROLE OF MITOCHONDRIA IN THE LIVER</a></li><li><a class="list_name" href="#body03">MITOCHONDRIAL DYSFUNCTION-MEDIATED METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE</a></li><li><a class="list_name" href="#body04">NEW THERAPEUTICS FOR MASLD</a></li><li><a class="list_name" href="#body05">CONCLUSION</a></li><li><a class="list_name" href="#body06">CONFLICTS OF INTEREST</a></li><li><a class="list_name" href="#body07">ACKNOWLEDGMENTS</a></li><li><a class="list_name" href="#body08">AUTHOR CONTRIBUTIONS</a></li><li><a class="list_name" href="#body09">Figure</a></li><li><a class="list_name" href="#body10">Table</a></li><li><a class="list_name" href="#body11">References</a></li></ul> </div> </div><div class="go_section" id="fulltext_Area"><div style="margin:5px;"><h3>Role of mitochondrial dysfunction in MASLD</h3> <p>In MASLD, hepatic mitochondria are structurally and molecularly altered.<sup><span class='xref'><a href="#B55" class="tooltip-img" title="">55</a></span></sup> Mitochondrial abnormalities, including altered cristae and reduced ATP production, have been observed in both mice and human studies.<sup><span class='xref'><a href="#B55" class="tooltip-img" title="">55</a></span></sup> In patients with MASH, mitochondria have low maximal respiration, increased H<sub>2</sub>O<sub>2</sub> production, lipid peroxidation, and decreased antioxidant capacity.<sup><span class='xref'><a href="#B56" class="tooltip-img" title="">56</a></span></sup> Therefore, mitochondria have been implicated in the pathogenesis and progression of MASLD.<sup><span class='xref'><a href="#B57" class="tooltip-img" title="">57</a></span></sup></p> <p>Mitochondrial dysfunction exacerbates hepatic lipid accumulation, initiates inflammatory and fibrogenic responses, and induces cell death. Obesity resulting from overnutrition causes an excess of free fatty acids (FFAs)<sup><span class='xref'><a href="#B58" class="tooltip-img" title="">58</a></span></sup> in the circulation, and elevated levels of FFAs in hepatocytes are characteristic of MASLD. Although liver mitochondria initially attempt to increase the oxidation of fatty acids to counteract the augmented fat accumulation, this compensatory response is insufficient to manage the increasing hepatic burden of FFAs. Excess FFAs are subsequently directed to triglyceride synthesis, resulting in the development of steatosis and hypertriglyceridemia.<sup><span class='xref'><a href="#B57" class="tooltip-img" title="">57</a></span>,<span class='xref'><a href="#B59" class="tooltip-img" title="">59</a></span></sup></p> <p>As steatosis progresses, there is a significant reduction in the mitochondrial redox capacity, which is primarily responsible for the impairment of respiratory chain function. Increased mitochondrial fatty acid delivery can lead to elevated level of uncoupled protein 2.<sup><span class='xref'><a href="#B60" class="tooltip-img" title="">60</a></span></sup> This elevation results in increased mitochondrial respiration and decreased ATP synthesis, which result in increased ROS generation. The resulting ROS can impair the respiratory chain activity and induce mutations in mtDNA, which contribute to mitochondrial dysfunction.<sup><span class='xref'><a href="#B61" class="tooltip-img" title="">61</a></span></sup></p> <p>When the efficiency of the respiratory chain declines, mitochondria are unable to completely oxidize excess FFAs. Therefore, extramitochondrial oxidation is an important pathway of FFA degradation, leading to the production of lipid peroxidation products and additional ROS.<sup><span class='xref'><a href="#B62" class="tooltip-img" title="">62</a></span></sup> These lipid peroxidation products damage mtDNA and crucial mitochondrial proteins, such as cytochrome C oxidase and adenine nucleotide translocator.<sup><span class='xref'><a href="#B63" class="tooltip-img" title="">63</a></span></sup> This damage culminates in a cascading cycle of mitochondrial impairment, increased lipid peroxidation, and heightened ROS production. The augmented production of ROS can stimulate inflammation directly by activating diverse inflammatory signaling pathways, including NF-κB and c-Jun N-terminal kinase (JNK), and indirectly by upregulating the expression of inflammatory cytokines, such as tumor necrosis factor-α and transforming growth factor-β.<sup><span class='xref'><a href="#B64" class="tooltip-img" title="">64</a></span>,<span class='xref'><a href="#B65" class="tooltip-img" title="">65</a></span></sup> These inflammatory mediators subsequently potentiate various pathological outcomes.</p> <p>Recent studies have reported increased extracellular mtDNA levels in mice and humans with metabolic dysfunction-associated fatty liver disease (MAFLD).<sup><span class='xref'><a href="#B66" class="tooltip-img" title="">66</a></span></sup> The release of oxidized mtDNA contributes to inflammasome activation, establishing an association between mitochondrial dysfunction and perpetuation of the inflammatory response.<sup><span class='xref'><a href="#B67" class="tooltip-img" title="">67</a></span></sup> Within cytosolic and extracellular environments, mtDNA serves as a damage-associated molecular pattern, initiating and propagating an inflammatory response through several signaling pathways. The Toll-like receptor 9, inflammasome, and stimulator of interferon gene pathways play a significant role in this complex cascade.<sup><span class='xref'><a href="#B66" class="tooltip-img" title="">66</a></span></sup> Activation of these pathways enhances damage to hepatocytes and potentially spreads injurious effects to other organs.<sup><span class='xref'><a href="#B67" class="tooltip-img" title="">67</a></span></sup></p> <p>Mitochondrial dysfunction is also associated with ER stress response in the liver. ER stress is induced by reduced ATP level and elevated ROS levels, resulting in activation of the unfolded protein response. This activation upregulates hepatic enzymes involved in lipid synthesis, leading to an increase in hepatic fat accumulation.<sup><span class='xref'><a href="#B68" class="tooltip-img" title="">68</a></span></sup> In addition, it amplifies the JNK signaling pathway, creating a pro-inflammatory environment.</p> <h3>Genetic association between mitochondria and MASLD</h3> <p>Through a comprehensive investigation of genetic variations across large cohorts, genome-wide association studies (GWAS) have consistently revealed genetic loci and variants intricately associated with mitochondrial function and dynamics in the context of MAFLD pathogenesis.<sup><span class='xref'><a href="#B69" class="tooltip-img" title="">69</a></span></sup> Of the single-nucleotide polymorphisms related to MAFLD in GWAS, those located in mitochondrial genes were also associated with the risk of MASLD. Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme in liver physiology responsible for converting acetaldehyde into nontoxic acetic acid, which is essential for detoxification processes.<sup><span class='xref'><a href="#B70" class="tooltip-img" title="">70</a></span></sup> In addition to its canonical function, ALDH2 increases the antioxidant capacity of the liver.<sup><span class='xref'><a href="#B71" class="tooltip-img" title="">71</a></span></sup> ALDH2 activity can be impeded by oxidative stress, which may compromise its protective function, and ALDH2 inhibition has deleterious effects in a murine model of liver disease.<sup><span class='xref'><a href="#B71" class="tooltip-img" title="">71</a></span>-<span class='xref'><a href="#B73" class="tooltip-img" title="">73</a></span></sup> <italic>ALDH2</italic> rs671 polymorphism is positively associated with a high risk of MASLD in Chinese<sup><span class='xref'><a href="#B74" class="tooltip-img" title="">74</a></span></sup> and Japanese<sup><span class='xref'><a href="#B75" class="tooltip-img" title="">75</a></span></sup> subjects. Additionally, several cohort studies have revealed a significant association between <italic>ALDH2</italic> polymorphism and other liver diseases, such as alcoholic liver disease and hepatic cellular carcinoma.<sup><span class='xref'><a href="#B76" class="tooltip-img" title="">76</a></span></sup></p> <p>The sorting and assembly machinery component 50 (<italic>SAMM50</italic>) gene encodes a β-barrel protein that comprises a component of the sorting and assembly machinery (SAM) complex located in the outer membrane of mitochondria.<sup><span class='xref'><a href="#B77" class="tooltip-img" title="">77</a></span></sup> The SAM complex is responsible for β-barrel protein sorting and assembly, ensuring proper mitochondrial structure and functionality.<sup><span class='xref'><a href="#B77" class="tooltip-img" title="">77</a></span></sup> In human hepatoma cell lines, SAMM50 knockdown leads to increased lipid accumulation due to reduced fatty acid oxidation. In contrast, <italic>SAMM50</italic> overexpression boosts fatty acid oxidation and reduces intracellular lipid accumulation.<sup><span class='xref'><a href="#B78" class="tooltip-img" title="">78</a></span></sup> In a large multiethnic cohort, <italic>SAMM50</italic> polymorphisms, including rs2143571, rs3761472, rs2073080, rs738491, rs2073082, rs738409, rs738408, rs3747207, and rs44391686, were positively associated with an increased risk of MASLD.<sup><span class='xref'><a href="#B78" class="tooltip-img" title="">78</a></span>-<span class='xref'><a href="#B81" class="tooltip-img" title="">81</a></span></sup> In addition, polymorphisms in mitochondria-related genes, including fatty acid-binding protein 1, glycerol-3-phosphate acyltransferase, lysophospholipase-like 1, and mitochondrial amidoxime-reducing component 1, are significantly associated with MASLD (<span class="xref"><a href="#T1">Table 1</a></span>).<sup><span class='xref'><a href="#B74" class="tooltip-img" title="">74</a></span>,<span class='xref'><a href="#B78" class="tooltip-img" title="">78</a></span>-<span class='xref'><a href="#B84" class="tooltip-img" title="">84</a></span></sup> Taken together, these comprehensive data obtained from the GWAS emphasize the significant influence of mitochondrial involvement on MASLD formation. Ongoing and diligent efforts in GWAS will enable a deeper understanding of the complex interactions between mitochondrial mechanisms and MASLD development, triggering innovative therapeutic approaches.</p></div></div></div> <div class="origin_section03" id="body04"> <div class="section03_tit clear"> <h3>NEW THERAPEUTICS FOR MASLD</h3> <div class="goto_layer"> <a href="#n">Go to <i class="xi-caret-down-min"></i></a> <ul class="go_list"><li><a class="list_name" href="#body00">Abstract</a></li><li><a class="list_name" href="#body01">INTRODUCTION</a></li><li><a class="list_name" href="#body02">ROLE OF MITOCHONDRIA IN THE LIVER</a></li><li><a class="list_name" href="#body03">MITOCHONDRIAL DYSFUNCTION-MEDIATED METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE</a></li><li><a class="list_name" href="#body04">NEW THERAPEUTICS FOR MASLD</a></li><li><a class="list_name" href="#body05">CONCLUSION</a></li><li><a class="list_name" href="#body06">CONFLICTS OF INTEREST</a></li><li><a class="list_name" href="#body07">ACKNOWLEDGMENTS</a></li><li><a class="list_name" href="#body08">AUTHOR CONTRIBUTIONS</a></li><li><a class="list_name" href="#body09">Figure</a></li><li><a class="list_name" href="#body10">Table</a></li><li><a class="list_name" href="#body11">References</a></li></ul> </div> </div><div class="go_section" id="fulltext_Area"><div style="margin:5px;"><h3>Current clinical trials for MASLD</h3> <p>Currently, there are no U.S. Food and Drug Administration (FDA)-approved treatments for MASLD. However, potential treatment options are being actively researched.<sup><span class='xref'><a href="#B85" class="tooltip-img" title="">85</a></span></sup> Because mitochondrial dysfunction plays a central role in the pathological mechanisms underlying NAFLD, therapeutic approaches targeting the mitochondria have been developed in recent years. <span class="xref"><a href="#T2">Table 2</a></span> shows the clinical trials of mitochondria-targeting drugs for MASLD treatment.<sup><span class='xref'><a href="#B86" class="tooltip-img" title="">86</a></span>-<span class='xref'><a href="#B93" class="tooltip-img" title="">93</a></span></sup> Vitamin E is a potent antioxidant<sup><span class='xref'><a href="#B94" class="tooltip-img" title="">94</a></span></sup> that has been studied in human clinical trials for MASLD treatment.<sup><span class='xref'><a href="#B86" class="tooltip-img" title="">86</a></span>,<span class='xref'><a href="#B94" class="tooltip-img" title="">94</a></span>,<span class='xref'><a href="#B95" class="tooltip-img" title="">95</a></span></sup> It improves serum enzyme levels, liver steatosis, inflammation, and fibrosis in patients without type 2 diabetes mellitus at a high dose of 800 IU/day for 96 weeks.<sup><span class='xref'><a href="#B86" class="tooltip-img" title="">86</a></span></sup> Recent meta-analyses have suggested that vitamin E reduces transaminase activity and potentially improves non-alcoholic steatohepatitis (NASH) histopathology. However, there is no significant improvement in liver fibrosis. Vitamin E is not recommended for the treatment of MASH associated with diabetes, MASLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis.<sup><span class='xref'><a href="#B96" class="tooltip-img" title="">96</a></span></sup></p> <p>Metformin is the oldest and most widely used first-line antidiabetic drug.<sup><span class='xref'><a href="#B97" class="tooltip-img" title="">97</a></span></sup> Metformin has several pharmacological effects that have inspired researchers to develop and reuse this drug.<sup><span class='xref'><a href="#B98" class="tooltip-img" title="">98</a></span></sup> Although the details of its metabolism are not fully understood, mitochondria play a central role in the activity of metformin.<sup><span class='xref'><a href="#B98" class="tooltip-img" title="">98</a></span></sup> Metformin inhibits complex I-dependent respiration and mitochondrial glycerophosphate dehydrogenase and activates sirtuin 1 (SIRT1) and SIRT3.<sup><span class='xref'><a href="#B98" class="tooltip-img" title="">98</a></span></sup> It controls blood glucose levels by suppressing hepatic glucose production via AMP-activated protein kinase (AMPK) activation.<sup><span class='xref'><a href="#B99" class="tooltip-img" title="">99</a></span></sup> In several clinical trials,<sup><span class='xref'><a href="#B87" class="tooltip-img" title="">87</a></span>,<span class='xref'><a href="#B100" class="tooltip-img" title="">100</a></span></sup> metformin has been shown to have beneficial effects on fatty liver disease, despite the controversy in the effect of metformin on MASLD found in the meta-analysis of randomized controlled trials.<sup><span class='xref'><a href="#B101" class="tooltip-img" title="">101</a></span></sup> Another meta-analysis revealed that metformin decreased transaminase activities and total cholesterol level and improved insulin sensitivity.<sup><span class='xref'><a href="#B102" class="tooltip-img" title="">102</a></span></sup> However, metformin is not recommended for treatment of MAFLD or MASH due to unsuccessful outcomes in clinical trials. In contrast, clinical trials have highlighted the promising effects of various compounds, including betaine,<sup><span class='xref'><a href="#B88" class="tooltip-img" title="">88</a></span></sup> pentoxifylline,<sup><span class='xref'><a href="#B89" class="tooltip-img" title="">89</a></span></sup> liraglutide,<sup><span class='xref'><a href="#B90" class="tooltip-img" title="">90</a></span></sup> exenatide,<sup><span class='xref'><a href="#B91" class="tooltip-img" title="">91</a></span></sup> and semaglutide<sup><span class='xref'><a href="#B92" class="tooltip-img" title="">92</a></span></sup> in ameliorating MASLD.</p> <h3>Potential new mitochondrial targets for MASLD treatment</h3> <p>Recently, several new therapeutics targeting MQC have emerged with potential benefits established through integrative analyses in mice and humans. Nicotinamide adenine dinucleotide (NAD<sup>+</sup>) serves as a central redox factor in energy metabolism and is a substrate for several enzymes, including SIRT.<sup><span class='xref'><a href="#B103" class="tooltip-img" title="">103</a></span></sup> NAD<sup>+</sup> plays an essential role as a precursor of reduced NAD phosphate, a critical component of the antioxidant defense mechanism in humans.<sup><span class='xref'><a href="#B103" class="tooltip-img" title="">103</a></span></sup> Cellular NAD<sup>+</sup> is a critical component of mitochondrial quality through processes such as the mtUPR.<sup><span class='xref'><a href="#B104" class="tooltip-img" title="">104</a></span></sup> Furthermore, low NAD<sup>+</sup> level is significantly associated with an increased risk of MASLD development.<sup><span class='xref'><a href="#B105" class="tooltip-img" title="">105</a></span></sup> NAD<sup>+</sup>-boosting strategies are potential therapeutic targets for MASLD.<sup><span class='xref'><a href="#B104" class="tooltip-img" title="">104</a></span></sup> NAD<sup>+</sup> precursors, such as nicotinamide riboside and nicotinamide mononucleotide, are commercially available supplements.<sup><span class='xref'><a href="#B104" class="tooltip-img" title="">104</a></span></sup> In preclinical models of MASLD, oral administration of these precursors increases hepatic NAD<sup>+</sup> concentrations and consequently inhibits hepatic lipid accumulation.<sup><span class='xref'><a href="#B103" class="tooltip-img" title="">103</a></span></sup> This intervention also improves hepatic mitochondrial respiration, steatosis, and oxidative stress in preclinical NAFLD models.<sup><span class='xref'><a href="#B103" class="tooltip-img" title="">103</a></span>,<span class='xref'><a href="#B106" class="tooltip-img" title="">106</a></span>,<span class='xref'><a href="#B107" class="tooltip-img" title="">107</a></span></sup></p> <p>Urolithin A (UA) is an endogenous substance synthesized by intestinal microorganisms through metabolic conversion of ingested ellagitannins and ellagic acid, which are complex polyphenolic compounds found in several dietary sources, such as pomegranates, berries, and nuts.<sup><span class='xref'><a href="#B108" class="tooltip-img" title="">108</a></span></sup> UA promotes cellular health by enhancing mitophagy and mitochondrial competence and attenuating harmful inflammatory responses.<sup><span class='xref'><a href="#B108" class="tooltip-img" title="">108</a></span>,<span class='xref'><a href="#B109" class="tooltip-img" title="">109</a></span></sup> Recent studies have demonstrated the beneficial effects of UA supplementation on MASLD through regulation of the AMPK signaling pathway<sup><span class='xref'><a href="#B110" class="tooltip-img" title="">110</a></span>,<span class='xref'><a href="#B111" class="tooltip-img" title="">111</a></span></sup> and induction of lipophagy.<sup><span class='xref'><a href="#B112" class="tooltip-img" title="">112</a></span></sup></p> <p>Spermidine is a natural polyamine abundant in certain food sources, such as rice bran, soybeans, aged cheese, mushrooms, and broccoli.<sup><span class='xref'><a href="#B113" class="tooltip-img" title="">113</a></span></sup> This polyamine has demonstrated notable beneficial effects under various pathological conditions owing to its ability to enhance mitochondrial functionality. Spermidine supplementation improves mitochondrial respiration, preserves mitochondrial membrane potential, and facilitates ATP synthesis.<sup><span class='xref'><a href="#B113" class="tooltip-img" title="">113</a></span>,<span class='xref'><a href="#B114" class="tooltip-img" title="">114</a></span></sup> In a mouse model of diet-induced obesity (DIO), spermidine ameliorated DIO-induced hepatic steatosis by regulating AMPK signaling.<sup><span class='xref'><a href="#B115" class="tooltip-img" title="">115</a></span></sup> In mice with Western diet-induced MASH, spermidine supplementation significantly attenuated hepatic lipid accumulation, insulin resistance, hepatic inflammation, and fibrosis.<sup><span class='xref'><a href="#B116" class="tooltip-img" title="">116</a></span></sup></p> <p>Mitoquinone (MitoQ) is an antioxidant that targets the matrix surface of the inner mitochondrial membrane and is particularly effective against lipid peroxidation.<sup><span class='xref'><a href="#B13" class="tooltip-img" title="">13</a></span></sup> MitoQ supplementation increases the mitochondrial CL content, improves mitochondrial function, reduces oxidative damage, and prevents hepatic fat accumulation in animal models.<sup><span class='xref'><a href="#B117" class="tooltip-img" title="">117</a></span>-<span class='xref'><a href="#B119" class="tooltip-img" title="">119</a></span></sup> These studies have highlighted novel therapeutic strategies targeting MQC with promising results in preclinical models. However, strict clinical trials are required to confirm their efficacy and safety.</p></div></div></div> <div class="origin_section03" id="body05"> <div class="section03_tit clear"> <h3>CONCLUSION</h3> <div class="goto_layer"> <a href="#n">Go to <i class="xi-caret-down-min"></i></a> <ul class="go_list"><li><a class="list_name" href="#body00">Abstract</a></li><li><a class="list_name" href="#body01">INTRODUCTION</a></li><li><a class="list_name" href="#body02">ROLE OF MITOCHONDRIA IN THE LIVER</a></li><li><a class="list_name" href="#body03">MITOCHONDRIAL DYSFUNCTION-MEDIATED METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE</a></li><li><a class="list_name" href="#body04">NEW THERAPEUTICS FOR MASLD</a></li><li><a class="list_name" href="#body05">CONCLUSION</a></li><li><a class="list_name" href="#body06">CONFLICTS OF INTEREST</a></li><li><a class="list_name" href="#body07">ACKNOWLEDGMENTS</a></li><li><a class="list_name" href="#body08">AUTHOR CONTRIBUTIONS</a></li><li><a class="list_name" href="#body09">Figure</a></li><li><a class="list_name" href="#body10">Table</a></li><li><a class="list_name" href="#body11">References</a></li></ul> </div> </div><div class="go_section" id="fulltext_Area"><div style="margin:5px;"><p>The increasing global prevalence of MASLD, formerly known as NAFLD, is a pressing public health concern. A growing body of studies has highlighted the pivotal role of mitochondria in the etiology and progression of MASLD. These dynamic organelles serve as metabolic hubs regulating hepatic energy production, lipid metabolism, and redox homeostasis. Dysfunctional mitochondria, characterized by oxidative stress, impaired OxPhos, and defective quality control mechanisms, significantly contribute to lipid accumulation, inflammation, and fibrogenesis in the liver. GWAS have identified genetic loci related to mitochondrial function and dynamics that influence the risk of MASLD. These genetic associations highlight the complex interplay between mitochondrial genetics and MASLD susceptibility.</p> <p>Although there are currently no FDA-approved treatments for MASLD, ongoing clinical trials exploring therapeutic options have identified promising strategies, including vitamin E and metformin, which target mitochondrial dysfunction to attenuate hepatic lipid accumulation and inflammation. Recent advancements have revealed novel mitochondria-targeted therapeutics, such as NAD<sup>+</sup> precursors, UA, spermidine, and MitoQ. These compounds potentially improve MQC, mitigate oxidative stress, and restore metabolic balance (<span class='xref'><a href="#F1" title="">Fig. 1</a></span>).</p> <p>In conclusion, mitochondrial dysfunction plays a key role in the pathogenesis of MASLD. The concerted efforts of researchers, clinicians, and drug developers are of critical importance for the prevention and treatment of this disease. Translating novel mitochondria-targeted approaches into effective and safe therapies will reduce disease burden and improve the quality of life of patients with MASLD worldwide.</p></div></div></div> <div class="origin_section03" id="body06"> <div class="section03_tit clear"> <h3>CONFLICTS OF INTEREST</h3> <div class="goto_layer"> <a href="#n">Go to <i class="xi-caret-down-min"></i></a> <ul class="go_list"><li><a class="list_name" href="#body00">Abstract</a></li><li><a class="list_name" href="#body01">INTRODUCTION</a></li><li><a class="list_name" href="#body02">ROLE OF MITOCHONDRIA IN THE LIVER</a></li><li><a class="list_name" href="#body03">MITOCHONDRIAL DYSFUNCTION-MEDIATED METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE</a></li><li><a class="list_name" href="#body04">NEW THERAPEUTICS FOR MASLD</a></li><li><a class="list_name" href="#body05">CONCLUSION</a></li><li><a class="list_name" href="#body06">CONFLICTS OF INTEREST</a></li><li><a class="list_name" href="#body07">ACKNOWLEDGMENTS</a></li><li><a class="list_name" href="#body08">AUTHOR CONTRIBUTIONS</a></li><li><a class="list_name" href="#body09">Figure</a></li><li><a class="list_name" href="#body10">Table</a></li><li><a class="list_name" href="#body11">References</a></li></ul> </div> </div><div class="go_section" id="fulltext_Area"><div style="margin:5px;"><p>The authors declare no conflict of interest.</p></div></div></div> <div class="origin_section03" id="body07"> <div class="section03_tit clear"> <h3>ACKNOWLEDGMENTS</h3> <div class="goto_layer"> <a href="#n">Go to <i class="xi-caret-down-min"></i></a> <ul class="go_list"><li><a class="list_name" href="#body00">Abstract</a></li><li><a class="list_name" href="#body01">INTRODUCTION</a></li><li><a class="list_name" href="#body02">ROLE OF MITOCHONDRIA IN THE LIVER</a></li><li><a class="list_name" href="#body03">MITOCHONDRIAL DYSFUNCTION-MEDIATED METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE</a></li><li><a class="list_name" href="#body04">NEW THERAPEUTICS FOR MASLD</a></li><li><a class="list_name" href="#body05">CONCLUSION</a></li><li><a class="list_name" href="#body06">CONFLICTS OF INTEREST</a></li><li><a class="list_name" href="#body07">ACKNOWLEDGMENTS</a></li><li><a class="list_name" href="#body08">AUTHOR CONTRIBUTIONS</a></li><li><a class="list_name" href="#body09">Figure</a></li><li><a class="list_name" href="#body10">Table</a></li><li><a class="list_name" href="#body11">References</a></li></ul> </div> </div><div class="go_section" id="fulltext_Area"><div style="margin:5px;"><p>This research was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (2020R1C1C1004999), “GIST Research Institute IIBR” grants funded by the GIST in 2022, KHIDI-AZ Diabetes Research Program, Young Medical Scientist Research Grant through the Daewoong Foundation (DFY2107P), and by a National Research Council of Science & Technology (NST) grant by the Korean government (MSIT) (No. CAP23021-110).</p></div></div></div> <div class="origin_section03" id="body08"> <div class="section03_tit clear"> <h3>AUTHOR CONTRIBUTIONS</h3> <div class="goto_layer"> <a href="#n">Go to <i class="xi-caret-down-min"></i></a> <ul class="go_list"><li><a class="list_name" href="#body00">Abstract</a></li><li><a class="list_name" href="#body01">INTRODUCTION</a></li><li><a class="list_name" href="#body02">ROLE OF MITOCHONDRIA IN THE LIVER</a></li><li><a class="list_name" href="#body03">MITOCHONDRIAL DYSFUNCTION-MEDIATED METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE</a></li><li><a class="list_name" href="#body04">NEW THERAPEUTICS FOR MASLD</a></li><li><a class="list_name" href="#body05">CONCLUSION</a></li><li><a class="list_name" href="#body06">CONFLICTS OF INTEREST</a></li><li><a class="list_name" href="#body07">ACKNOWLEDGMENTS</a></li><li><a class="list_name" href="#body08">AUTHOR CONTRIBUTIONS</a></li><li><a class="list_name" href="#body09">Figure</a></li><li><a class="list_name" href="#body10">Table</a></li><li><a class="list_name" href="#body11">References</a></li></ul> </div> </div><div class="go_section" id="fulltext_Area"><div style="margin:5px;"><p>Study concept and design: CMO; acquisition of data: SS, JK, and JYL; drafting of the manuscript: SS, JK, and CMO; critical revision of the manuscript: CMO; obtained funding: CMO; administrative, technical, or material support: CMO; and study supervision: CMO.</p></div></div></div> <div class="origin_section03" id="body09"> <div class="section03_tit clear"> <h3>Figures</h3> <div class="goto_layer"> <a href="#n">Go to <i class="xi-caret-down-min"></i></a> <ul class="go_list"><li><a class="list_name" href="#body00">Abstract</a></li><li><a class="list_name" href="#body01">INTRODUCTION</a></li><li><a class="list_name" href="#body02">ROLE OF MITOCHONDRIA IN THE LIVER</a></li><li><a class="list_name" href="#body03">MITOCHONDRIAL DYSFUNCTION-MEDIATED METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE</a></li><li><a class="list_name" href="#body04">NEW THERAPEUTICS FOR MASLD</a></li><li><a class="list_name" href="#body05">CONCLUSION</a></li><li><a class="list_name" href="#body06">CONFLICTS OF INTEREST</a></li><li><a class="list_name" href="#body07">ACKNOWLEDGMENTS</a></li><li><a class="list_name" href="#body08">AUTHOR CONTRIBUTIONS</a></li><li><a class="list_name" href="#body09">Figure</a></li><li><a class="list_name" href="#body10">Table</a></li><li><a class="list_name" href="#body11">References</a></li></ul> </div> </div><div class="go_section" style='margin-top:15px;' id="fulltext_Area"> <div id='F1' style='margin-bottom:5px;'> <img width='100' src='https://pdf.medrang.co.kr/KSSO2/2023/032/thumb/jomes-32-4-289-f1.jpg' align='left' class='view_img pointer' onclick="popen('popup_file.html?uid=1032&file=jomes-32-4-289-f1.jpg&md=fig&idx=1','','840','800','yes');" ehref="https://pdf.medrang.co.kr/KSSO2/2023/032/thumb/jomes-32-4-289-f1.jpg" jhref="popup_file.html?uid=1032&file=jomes-32-4-289-f1.jpg&md=fig&idx=1" id="F1I" iwidth="" iheight="" style='cursor:pointer'/> <a href='popup_file.html?uid=1032&file=jomes-32-4-289-f1.jpg&md=fig&idx=1' class='j_text_size' onclick="popen(this.getAttribute('href'),'','840','800','yes'); return false;">Fig. 1.</a> Mitochondrial dysfunction in fatty liver. In fatty liver, stressed and damaged mitochondria cause greater oxidative stress and less energy production. New therapeutics that restore mitochondrial function could be a promising way to treat metabolic dysfunction-associated steatotic liver disease. GLP-1, glucagon-like peptide 1; NAD<sup>+</sup>, nicotinamide adenine dinucleotide; NR, nicotinamide riboside; NMN, nicotinamide mononucleotide; MitoQ, mitoquinone; ROS, reactive oxygen species; ATP, adenosine triphosphate. <br clear='all' /> </div></div></div> <div class="origin_section03" id="body10"> <div class="section03_tit clear"> <h3>Tables</h3> <div class="goto_layer"> <a href="#n">Go to <i class="xi-caret-down-min"></i></a> <ul class="go_list"><li><a class="list_name" href="#body00">Abstract</a></li><li><a class="list_name" href="#body01">INTRODUCTION</a></li><li><a class="list_name" href="#body02">ROLE OF MITOCHONDRIA IN THE LIVER</a></li><li><a class="list_name" href="#body03">MITOCHONDRIAL DYSFUNCTION-MEDIATED METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE</a></li><li><a class="list_name" href="#body04">NEW THERAPEUTICS FOR MASLD</a></li><li><a class="list_name" href="#body05">CONCLUSION</a></li><li><a class="list_name" href="#body06">CONFLICTS OF INTEREST</a></li><li><a class="list_name" href="#body07">ACKNOWLEDGMENTS</a></li><li><a class="list_name" href="#body08">AUTHOR CONTRIBUTIONS</a></li><li><a class="list_name" href="#body09">Figure</a></li><li><a class="list_name" href="#body10">Table</a></li><li><a class="list_name" href="#body11">References</a></li></ul> </div> </div> <div id='T1' class='table-responsive'><label>Table 1</label> <p>List of mitochondrial single-nucleotide polymorphism sites associated with MASLD</p> <table frame="hsides" rules="groups"> <thead> <tr> <th valign="middle" align="center">Gene</th> <th valign="middle" align="center">Name</th> <th valign="middle" align="center">Polymorphism</th> <th valign="middle" align="center">Association with MASLD</th> <th valign="middle" align="center">Cohort</th> <th valign="middle" align="center">Reference</th> </tr> </thead> <tbody> <tr> <td valign="top" align="left"><italic>ALDH2</italic></td> <td valign="top" align="left">Aldehyde dehydrogenase 2</td> <td valign="top" align="left">rs671</td> <td valign="top" align="left">Associated with increased probability of MASLD</td> <td valign="top" align="left">Chinese patients with MASLD</td> <td valign="top" align="left"><sup><span class="xref"><sup><a href="#B74">74</a></sup></span></sup></td> </tr> <tr> <td valign="top" align="left"><italic>FABP1</italic></td> <td valign="top" align="left">Fatty acid-binding protein 1</td> <td valign="top" align="left">rs72943235</td> <td valign="top" align="left">Associated with increased risk of fibrosis</td> <td valign="top" align="left">Participants from the Electronic Medical Records and Genomics (eMERGE) Network</td> <td valign="top" align="left"><sup><span class="xref"><sup><a href="#B79">79</a></sup></span></sup></td> </tr> <tr> <td valign="top" align="left"><italic>GPAM</italic></td> <td valign="top" align="left">Glycerol-3-phosphate acyltransferase</td> <td valign="top" align="left">rs2792751</td> <td valign="top" align="left">Associated with steatosis and liver damage</td> <td valign="top" align="left">UK Biobank samples</td> <td valign="top" align="left"><sup><span class="xref"><sup><a href="#B82">82</a></sup></span></sup></td> </tr> <tr> <td valign="top" align="left"><italic>LYPLAL1</italic></td> <td valign="top" align="left">Lysophospholipas-like 1</td> <td valign="top" align="left">rs12137855</td> <td valign="top" align="left">Associated with increased risk of steatosis and fibrosis</td> <td valign="top" align="left">Young and middle-aged Finns</td> <td valign="top" align="left"><sup><span class="xref"><sup><a href="#B83">83</a></sup></span></sup></td> </tr> <tr> <td valign="top" align="left"><italic>MTARC1</italic></td> <td valign="top" align="left">Mitochondrial amidoxime-reducing component 1</td> <td valign="top" align="left">rs2642438</td> <td valign="top" align="left">Independent protective factor against fibrosis</td> <td valign="top" align="left">Caucasian Polish patients who underwent liver biopsy during weight loss surgery</td> <td valign="top" align="left"><sup><span class="xref"><sup><a href="#B84">84</a></sup></span></sup></td> </tr> <tr> <td valign="top" align="left"><italic>SAMM50</italic></td> <td valign="top" align="left">Sorting and assembly machinery component 50 homolog</td> <td valign="top" align="left">rs2143571<br> rs3761472<br> rs2073080</td> <td valign="top" align="left">Associated with the presence and severity of MASLD</td> <td valign="top" align="left">Korean patients with MASLD</td> <td valign="top" align="left"><sup><span class="xref"><sup><a href="#B80">80</a></sup></span></sup></td> </tr> <tr> <td> </td><td> </td><td valign="top" align="left">rs738491<br> rs2073082</td> <td valign="top" align="left">Risk and severity of MASLD</td> <td valign="top" align="left">Chinese Han patients with MASLD</td> <td valign="top" align="left"><sup><span class="xref"><sup><a href="#B78">78</a></sup></span></sup></td> </tr> <tr> <td> </td><td> </td><td valign="top" align="left">rs738409<br> rs738408<br> rs3747207</td> <td valign="top" align="left">Associated with MASLD risk</td> <td valign="top" align="left">Participants from the eMERGE Network</td> <td valign="top" align="left"><sup><span class="xref"><sup><a href="#B79">79</a></sup></span></sup></td> </tr> <tr> <td> </td><td> </td><td valign="top" align="left">rs44391686</td> <td valign="top" align="left">Associated with MASLD risk</td> <td valign="top" align="left">Patients with MASLD from five ethnic groups</td> <td valign="top" align="left"><sup><span class="xref"><sup><a href="#B81">81</a></sup></span></sup></td> </tr> </tbody> </table> <table-wrap-foot> <fn id="t1fn1"><p>MASLD, metabolic steatosis-associated steatotic liver disease; PNPLA3, patatin like phospholipase domain containing 3.</p></fn> </table-wrap-foot></div> <div id='T2' class='table-responsive'><label>Table 2</label> <p>Selected clinical trials of mitochondria-centric drugs</p> <table frame="hsides" rules="groups"> <thead> <tr> <th valign="middle" align="center" rowspan="2">Drug</th> <th valign="middle" align="center" rowspan="2">Author (year)</th> <th valign="middle" align="center" rowspan="2">National Clinical Trial numbers</th> <th valign="middle" align="center" rowspan="2">Mechanism of action</th> <th valign="middle" align="center" colspan="2" style="border-bottom:solid 1px;">Study outcomes</th> </tr> <tr> <th valign="middle" align="center">Liver enzymes</th> <th valign="middle" align="center">Histology</th> </tr> </thead> <tbody> <tr> <td valign="top" align="left">Vitamin E</td> <td valign="top" align="left">Sanyal et al. (2010)<sup><span class="xref"><sup><a href="#B86">86</a></sup></span></sup></td> <td valign="top" align="left">NCT00063622<br> NCT02690792<br> NCT01792115<br> NCT02962297<br> NCT04198805<br> NCT01147523<br> NCT01934777<br> NCT00655018</td> <td valign="top" align="left">Restoration the hepatic glutathione level</td> <td valign="top" align="left">Improved</td> <td valign="top" align="left">Improved steatosis and inflammation</td> </tr> <tr> <td valign="top" align="left">Metformin</td> <td valign="top" align="left">Loomba et al. (2009)<sup><span class="xref"><sup><a href="#B87">87</a></sup></span></sup></td> <td valign="top" align="left">NCT00063232<br> NCT00736385<br> NCT02696941<br> NCT05521633</td> <td valign="top" align="left">Activation of AMPK signaling</td> <td valign="top" align="left">Improved</td> <td valign="top" align="left">Improved parenchymal inflammation and cellular injury</td> </tr> <tr> <td valign="top" align="left">Resveratrol</td> <td valign="top" align="left">Faghihzadeh et al. (2014)<sup><span class="xref"><sup><a href="#B93">93</a></sup></span></sup></td> <td valign="top" align="left">NCT01446276<br> NCT02030977<br> NCT01464801<br> NCT02216552</td> <td valign="top" align="left">Activation of mitochondrial biogenesis and mitochondria-located antioxidant enzymes</td> <td valign="top" align="left">Improved</td> <td valign="top" align="left">Improved hepatic steatosis</td> </tr> <tr> <td valign="top" align="left">Betaine</td> <td valign="top" align="left">Abdelmalek et al. (2009)<sup><span class="xref"><sup><a href="#B88">88</a></sup></span></sup></td> <td valign="top" align="left">NCT00586911<br> NCT03073343</td> <td valign="top" align="left">Restoration of hepatic mitochondrial glutathione and S-adenosyl methionine</td> <td valign="top" align="left">No improvement</td> <td valign="top" align="left">Improved hepatic steatosis</td> </tr> <tr> <td valign="top" align="left">Pentoxifylline</td> <td valign="top" align="left">Zein et al. (2011)<sup><span class="xref"><sup><a href="#B89">89</a></sup></span></sup></td> <td valign="top" align="left">NCT00267670<br> NCT00590161<br> NCT05284448</td> <td valign="top" align="left">Increasing Nrf2 and PGC-1α through the cAMP–CREB pathway</td> <td valign="top" align="left">No improvement</td> <td valign="top" align="left">Improved steatosis, inflammation, and fibrosis</td> </tr> <tr> <td valign="top" align="left">Liraglutide</td> <td valign="top" align="left">Armstrong et al. (2016)<sup><span class="xref"><sup><a href="#B90">90</a></sup></span></sup></td> <td valign="top" align="left">NCT02147925<br> NCT03068065<br> NCT01399645<br> NCT03233178<br> NCT01237119<br> NCT05041673<br> NCT05779644<br> NCT02654665</td> <td valign="top" align="left">Enhancing mitochondrial architecture through the SIRT1/SIRT3 signaling</td> <td valign="top" align="left">Improved</td> <td valign="top" align="left">Improved hepatic steatosis</td> </tr> <tr> <td valign="top" align="left">Exenatide</td> <td valign="top" align="left">Liu et al. (2021)<sup><span class="xref"><sup><a href="#B91">91</a></sup></span></sup></td> <td valign="top" align="left">NCT02303730<br> NCT01006889<br> NCT01208649<br> NCT00650546<br> NCT00529204</td> <td valign="top" align="left">Enhancing mitochondrial architecture through the SIRT1/SIRT3 signaling</td> <td valign="top" align="left">Improved</td> <td valign="top" align="left">Improved hepatic steatosis</td> </tr> <tr> <td valign="top" align="left">Semaglutide</td> <td valign="top" align="left">Newsome et al. (2021)<sup><span class="xref"><sup><a href="#B92">92</a></sup></span></sup></td> <td valign="top" align="left">NCT02970942</td> <td valign="top" align="left">Enhancing mitochondrial architecture through the SIRT1/SIRT3 signaling</td> <td valign="top" align="left">Improved</td> <td valign="top" align="left">Improved hepatic fibrosis and reduced liver-enzyme levels</td> </tr> </tbody> </table> <table-wrap-foot> <fn id="t2fn1"><p>AMPK, AMP-activated protein kinase; Nrf2, nuclear factor erythroid 2-related factor 2; PGC-1α, peroxisome proliferator-activated receptor-γ coactivator-1α; cAMP, cyclic adenosine monophosphate; CREB, cAMP-response element binding protein; SIRT1, sirtuin 1; SIRT3, sirtuin 3.</p></fn> </table-wrap-foot></div></div> <div class="origin_section03" id="body11"> <div class="section03_tit clear"> <h3>References</h3> <div class="goto_layer"> <a href="#n">Go to <i class="xi-caret-down-min"></i></a> <ul class="go_list"><li><a class="list_name" href="#body00">Abstract</a></li><li><a class="list_name" href="#body01">INTRODUCTION</a></li><li><a class="list_name" href="#body02">ROLE OF MITOCHONDRIA IN THE LIVER</a></li><li><a class="list_name" href="#body03">MITOCHONDRIAL DYSFUNCTION-MEDIATED METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE</a></li><li><a class="list_name" href="#body04">NEW THERAPEUTICS FOR MASLD</a></li><li><a class="list_name" href="#body05">CONCLUSION</a></li><li><a class="list_name" href="#body06">CONFLICTS OF INTEREST</a></li><li><a class="list_name" href="#body07">ACKNOWLEDGMENTS</a></li><li><a class="list_name" href="#body08">AUTHOR CONTRIBUTIONS</a></li><li><a class="list_name" href="#body09">Figure</a></li><li><a class="list_name" href="#body10">Table</a></li><li><a class="list_name" href="#body11">References</a></li></ul> </div> </div><div class="go_section" id="fulltext_Area"> <ol style='width:97%; padding-top:15px;padding-left:20px;'> <li id='B1' style='list-style-type:decimal;padding-bottom: 10px;'><div class='j_text_size'>Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F, et al. 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